PROJECT SUMMARY We have recently identified homozygous loss of function mutations in the complement regulatory protein CD55 in two unrelated individuals suffering from early onset inflammatory bowel disease. Mouse models have previously shown that CD55 deficiency leads to hyper activation of T cells in response to antigen and the enhanced secretion of inflammatory cytokines associated with development of more severe EAE and DSS induced colitis than wild type counter parts. This would suggest that the signaling pathways, either related to CD55's complement regulatory activity or its ability to function as a costimulatory molecule, leading to disease in CD55 deficient individuals are conserved across species and represent very promising therapeutic targets. Importantly, our preliminary data show a lack of CD55 on patient T cells is associated with a drastic upregulation of cytokine production including those traditionally associated with Th1 and Th2 responses. Based on the literature and on our preliminary data, we hypothesize that CD55 is critical for proper regulation of local complement activation and that its absence leads to complement mediated immune dysfunction and failure of epithelial barriers. This hypothesis will be tested by carrying out the following three specific aims designed to determine the cause of disease, and test the modulation of this pathway as a potential therapeutic intervention in IBD. In Aim 1 we will determine the role of CD55 in T cell activation, differentiation, and cytokine production through use of CD55 deficient and healthy normal donor cells and specific complement inhibitors including small molecule and blocking antibodies. In Aim 2 we will evaluate the role of CD55 in maintaining gut epithelial barrier integrity and promoting intestinal restitution and wound repair. Finally, in Aim 3 we will investigate the role of complement and CD55 in mouse models of IBD and their potential as therapeutic targets. Together these studies will provide mechanistic insight into the function of CD55 in immune cell and epithelial cell activation and homeostasis. Additionally, this work will evaluate the use of complement modulating therapies for the treatment of IBD in our patient population and in otherwise healthy individuals. Additionally, the activities planned under this award will provide an essential training opportunity that will position the applicant for success as an independent researcher at an academic institution studying the mechanisms of T cell signaling and activation during the immune response.